Progressive Malignant Brain Tumors Research Articles

Targeting oncometabolism to maximize immunotherapy in malignant brain tumors.

Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicates that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed ‘tumor immunometabolism’. Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase (IDO), and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.

Stereotactic Placement of Intratumoral Catheters for Continuous Infusion Delivery of Herpes Simplex Virus -1 G207 in Pediatric Malignant Supratentorial Brain Tumors

The engineered herpes simplex virus-1 G207, is a promising therapeutic option for central nervous system tumors. The first-ever pediatric phase 1 trial of continuous-infusion delivery of G207 via intratumoral catheters for recurrent or progressive malignant brain tumors is ongoing. In this article, we describe surgical techniques for the accurate placement of catheters in multiple supratentorial locations and perioperative complications associated with such procedures. A prospective study of G207 in children with recurrent malignant supratentorial tumors is ongoing. Preoperative stereotactic protocol magnetic resonance imaging was performed, and catheter trajectories planned using StealthStation planning software. Children underwent placement of 3-4 silastic catheters using a small incision burr hole and the Vertek system. Patients had a preinfusion computed tomography scan to confirm correct placement of catheters. Six children underwent implantation of 3-4 catheters. Locations of catheter placement included frontal, temporal, parietal, and occipital lobes, and the insula and thalamus. There were no clinically significant perioperative complications. Postoperative computed tomography scans coupled with preoperative MRI scans demonstrated accurate placement of 21 of 22 catheters, with 1 misplaced catheter pulled back to an optimal location at the bedside. One patient had hemorrhage along the catheter tract that was clinically asymptomatic. Another patient had cerebrospinal fluid leak from a biopsy incision 9 days after surgery that was oversewn without complication. The placement of multiple intratumoral catheters in pediatric patients with supratentorial tumors via frameless stereotactic techniques is feasible and safe. Intratumoral catheters provide a potentially effective route for the delivery of G207 and may be employed in other trials utilizing oncolytic virotherapy for brain tumors.

Abstract CT004: Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy

Abstract BACKGROUND: In theory, combining immunotherapy with radiation (RT) and chemotherapy is an appealing therapeutic strategy that may offer potential synergistic benefits. The indoleamine 2,3-dioxygenase (IDO) pathway regulates inflammation and immune responses to apoptotic cells. Indoximod reverses the profound immunosuppression created by IDO in the tumor microenvironment. METHODS: 29 pediatric patients with recurrent or progressive malignant brain tumors were treated in two separate indoximod dose-escalation cohorts. Patients eligible for re-irradiation (re-RT) (17/29) were treated with conformal RT (15-54 Gy) in combination with indoximod, followed by indoximod with cyclic temozolomide (200 mg/m2/day for the first 5 days of each 28-day cycle). Patients not eligible for RT received indoximod plus cyclic temozolomide. After initial response or disease stabilization (at least 4 months), patients who showed progression were offered planned re-RT to escape lesions, surgical debulking where indicated, and cross-over to an alternative chemotherapy regimen (oral metronomic cyclophosphamide plus etoposide) while continuing indoximod immunotherapy. Time to Regimen Failure (TTRF) was used to capture time on study. RESULTS: In aggregate, 29 relapsed patients had a median PFS of 6.2 months, median time on study (TTRF) was 11.7 months, and 9/29 are continuing treatment. Patients given RT had median TTRF 13.5 months vs. 4.3 months for no RT. Patients not eligible for conventional full-dose re-RT (>50 Gy) received lower-dose RT (=<30 Gy) not attempting to target all disease where that would be toxic. 9 of 17 patients received lower-dose, restricted-field RT and median TTRF was 16 months versus 13 months for full-dose RT. Based on these results, a cohort of newly-diagnosed patients with diffuse intrinsic pontine glioma (DIPG) was opened using indoximod during front-line RT (54 Gy) followed by maintenance indoximod plus temozolomide. To date 6 newly-diagnosed DIPG patients have enrolled, all with bulbar signs and bulky disease on MRI at study entry. The first 3 newly-diagnosed DIPG patients have completed induction radio-immunotherapy which was well tolerated with symptomatic improvement in all patients, radiographic responses in 3/3, and near resolution of one tumor at the end of radiotherapy. An additional patient with progressive DIPG received re-RT (27 Gy) combined with indoximod, which was tolerated well with symptomatic improvement and objective tumor reduction on post-RT MRI. CONCLUSIONS: Indoximod was well-tolerated in combination with RT and chemotherapy. TTRF compares favorably with historical controls. Lower-dose, restricted-field RT may be beneficial when combined with indoximod in relapse cases. Front-line studies have begun in a cohort of DIPG patients. Citation Format: Theodore S. Johnson, Dolly Aguilera, Ahmad Al-Basheer, Robert C. Castellino, Bree R. Eaton, Natia Esiashvili, Nicholas Foreman, Ian M. Heger, Eugene P. Kennedy, Charles J. Link, William Martin, Eric K. Ring, Ramses F. Sadek, Amy Smith, Vahanian N. Vahanian, Tobey J. MacDonald, David H. Munn. Front-line therapy of DIPG using the IDO pathway inhibitor indoximod in combination with radiation and chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT004.

Corticosteroids in brain cancer patients: benefits and pitfalls

Glucocorticoids have been used for decades in the treatment of brain tumor patients and belong to the most powerful class of agents in reducing tumor-associated edema and minimizing side effects and the risk of encephalopathy in patients undergoing radiation therapy. Unfortunately, corticosteroids are associated with numerous and well-characterized adverse effects, constituting a major challenge in patients requiring long-term application of corticosteroids. Novel anti-angiogenic agents, such as bevacizumab (Avastin®), which have been increasingly used in cancer patients, are associated with significant steroid-sparing effects, allowing neuro-oncologists to reduce the overall use of corticosteroids in patients with progressive malignant brain tumors. Recent experimental studies have revealed novel insights into the mechanisms and effects of corticosteroids in cancer patients, including modulation of tumor biology, angiogenesis and steroid-associated neurotoxicity. This article summarizes current concepts of using corticosteroids in brain cancer patients and highlights potential pitfalls in their effects on both tumor and neural progenitor cells.

A volumetric study of CyberKnife hypofractionated stereotactic radiotherapy as salvage for progressive malignant brain tumors: initial experience

Objective: Radiosurgery is frequently offered to patients with progressive malignant brain tumors if radiation therapy or chemotherapy fails to provide local control. The use of single-shot regimens, however, is limited by the risk of complications when the tumor is large, surrounded by edema or has been pre-treated with radiation. Hypofractionation may confer safety but has not been tested for these difficult tumors. We report the results of hypofractionation as an alternative option in a small cohort of progressive malignant brain tumors.Methods: Hypofractionated CyberKnife radiotherapy was chosen for 18 progressive malignant brain tumors (six high-grade gliomas and 12 metastatic lesions) in 15 patients because of size, previous treatment with radiation or surrounding edema. The mean dose was 21 ± 4 Gy and the number of fractions was 5 ± 0.6. The volume of each tumor at treatment was compared with the volume at follow-up.Results: Thirteen of the 18 tumors (72%) showed a volume decrease. The average volume change was a decrease of 16 ± 58% (median: 20%) with a follow-up of 180 ± 121 days (median: 172 days). Toxicity occurred in only one patient, with symptoms improving on steroids.Discussion: Progression of malignant brain tumors not ideal for single-shot radiosurgery can be arrested or reversed, at least for short periods, with minimal toxicity using hypofractionated radiotherapy. Longer studies will be needed to assess durability of this response in these difficult tumors.

Second-line chemotherapy with the association of liposomal daunorubicin, carboplatin and etoposide in children with recurrent malignant brain tumors.

Progressive or recurrent high-grade gliomas are characterized by a very poor prognosis, and the relevance of second-line chemotherapy is still unassessed. Although it has been reported that liposomal anthracyclines and carboplatin show some activity in these patients, their association has never been investigated. We have treated six children with recurrent high-grade glioma after surgery, radiotherapy and chemotherapy, and one child with progressive teratoid/rhabdoid tumor with the combination of liposomal daunorubicin and carboplatin plus etoposide. Five out of seven children showed a major response and the 29 month progression-free survival was 38%. The above regimen was feasible and children showed only little and transient hematological toxicity. In our opinion, these results justify further investigation of the above combination chemotherapy for recurrent or progressive malignant brain tumors in children.

Safety and efficacy of concurrent interstitial radiation and hyperthermia in the treatment of progressive malignant brain tumors

High activity 125I brachytherapy has efficacy in selected recurrent malignant brain tumors, but limited efficacy and risk of radiation necrosis have prompted investigation of additional adjunctive therapies. This study aims to assess the toxicity of interstitial conductive hyperthermia used concurrently with 125I brachytherapy for the treatment of recurrent brain malignancies. Twelve patients with recurrent malignant brain tumors were implanted using afterloading catheters intended to deliver 50 Gy at the isodose line encompassing the enhancing tumor with a 5-mm margin and heated to 41.5 degrees C for 48 h. The average implant volume was 18 cc with 5.3 catheters containing 9.4 sources with a total activity of 265 mCi. Serious toxicities included 8 motor deficits, 2 mood alterations, 4 seizures and 2 catheter wound cerebrospinal fluid leaks. Median survival was 10.35 months with the best responses being 6 with stable disease and 2 with partial responses. Reoperation rate for radiation necrosis was 33%. Concurrent conductive thermoradiotherapy is feasible but is associated with serious toxicity. There is no suggestion of improved survival with thermoradiotherapy over brachytherapy alone. Given the degree of toxicity observed, alternative approaches to improving local control of these tumors are being explored.

CLINICAL AND RADIOGRAPHIC RESPONSE IN THREE CHILDREN WITH RECURRENT MALIGNANT CEREBRAL TUMORS WITH HIGH-DOSE TAMOXIFEN

The purpose of this study was to deliver tamoxifen as antiangiogenic therapy to children with recurrent progressive malignant brain tumors. Tamoxifen was administered orally in very high dosage to one child as monotherapy and to two children in combination with oral etoposide and dexamethasone. One boy was diagnosed with high-grade astrocytoma in the brain stem, one girl with anaplastic ependymoma of the fourth ventricule, and one girl with high-grade astrocytoma in the midbrain. Conventional treatment with multiple surgeries, first- and second-line chemotherapy, and external beam therapy had failed. Tumor reduction was seen in radiographic images together with clinical improvement in 2 children, and clinical and radiographic halting of tumor progression was demonstrated in the patient with anaplastic ependymoma. None of the patients developed complications from the treatment. Follow up of the patients ranged from 15 to 30 months with a mean of 17 months. These encouraging preliminary results suggest a potential for this type of therapy. More studies are needed to start clinical trials and prove that angiostatic activity may contribute to the therapeutic effect of antiestrogens in estrogen receptor-negative tumors.

High-dose melphalan and cyclophosphamide with autologous bone marrow rescue for recurrent/progressive malignant brain tumors in children: a pilot pediatric oncology group study.

To determine the maximum-tolerated dose of cyclophosphamide (CTX) when administered sequentially with melphalan 60 mg/m2/d for 3 days, followed by autologous bone marrow rescue (ABMR), in children with recurrent or progressive malignant brain tumors, and to make preliminary observations on efficacy. Nineteen patients between the ages of 2 and 21 years were enrolled and 18 were assessable for effects of therapy. CTX was administered to seven patients at 750 mg/m2/d for 4 days, to five patients at 975 mg/m2/d, to three patients at 1,200 mg/m2/d, and to three patients at 1,500 mg/m2/d. All patients received ABMR. Granulocyte-macrophage colony-stimulating factor (GM-CSF) was used in 15 patients. Toxicity, response to therapy, time to progression, and survival and monitored. The median time to a granulocyte count more than 500/dL was 19 days (range, 11 to 39), and for a platelet count more than 50,000/dL was 33 days (range, 16 to 60). Four heavily pretreated patients (22%) died of transplant-related complications. No dose-limiting, non-hematologic toxicities were defined for the study. Seven of 18 patients (39%) had a complete response (CR) or a partial response (PR). These included four patients with medulloblastoma (CR and three PRs), two with germinomas (two CRs), and one with ependymoma (one CR). The estimated 1-year survival rate was 39% (SE 12%). CTX, at a maximum total dose of 6,000 mg/m2, administered sequentially with melphalan and followed by ABMR was tolerable in children with recurrent brain tumors who had not been heavily pretreated. Responses were seen in patients with medulloblastoma and germinomas. Further trials in children with chemosensitive tumors, with minimal residual disease, are planned.

Effect of human leukocyte interferon on malignant brain tumors.

The antitumor effect of human leukocyte interferon was investigated on ten patients with malignant brain tumor. In eight cases of primary tumor, IFN alone was administered when their recurrent sign was evident. A dose of 3 X 10(6) IU or 1 X 10(6) IU of IFN was injected intramuscularly two or three times a week in high-dose group, while a dose of 5 X 10(4) IU once a week in low-dose group. No remarkable side effects including bone marrow depression were noted. Natural killer activity was enhanced and immunologic skin reaction manifested. Partial remission of more than 50% decrease of tumor volume calculated on CT scan was seen in two cases in the low-dose group for about 3-6 months. Complete remission could not be obtained by IFN alone. Our pilot study has shown that IFN alone will not be effective against progressive malignant brain tumors by general administration. Further investigation should be carried out to improve the use of IFN therapy in malignant brain tumor.